The present invention relates to monensin urethane derivatives of the formula ##STR2## wherein R.sub.1 is hydrogen, wherein R.sub.4 is alkyl, aryl, alkylaryl, arylalkyl, haloaryl, nitroaryl, haloarylalkyl, alkoxyaryl, aryloxyaryl, arylcycloalkyl, acylaryl and cycloalkyl; R.sub.2 is methyl or ethyl and R.sub.3 is --CONHR.sub.4 and their pharmaceutically acceptable salts.
The shorthand expression Me is utilized throughout to represent methyl.
The compounds of the present invention and their salts exhibit activity as antibacterial agents, growth promotant agents in ruminants, coccidiostats, antihypertensives, antimalarial agents and as agents in the treatment of swine dysentery.
By the term "acyl" is meant a C.sub.1 to C.sub.7, preferably a C.sub.1 to C.sub.4 alkanoic acid moiety, i.e., radicals of the formula ##STR3## wherein R is C.sub.1 to C.sub.6 or hydrogen, e.g., acetyl, propionyl, butyryl and the like.
By the term "cycloalkyl" is meant cyclic hydrocarbon groups containing from 3 to 7 carbon atoms, such as, cyclopropyl, cyclobutyl, cyclohexyl and the like with cyclohexyl as preferred. The cycloalkyl group may be substituted by an aryl residue as defined herein to form an arylcycloalkyl residue, e.g., 2-(phenyl)-cyclopropyl.
By the term "alkoxy" is meant a C.sub.1 to C.sub.7 lower alkyl group having an oxygen function substituted therein, such as, methoxy, ethoxy, propoxy and the like.
The term "aryl" denotes an aromatic residue derived by the removal of a hydrogen atom from an aromatic hydrocarbon, such as, for example, phenyl, pyridyl or furyl, especially phenyl. Thereafter the "aryl" residue may be substituted by various groups. A substituent on a phenyl nucleous is preferably in 4-position such as in 4-alkylaryl, e.g., 4-methylphenyl(4-tolyl), 4-halophenyl, e.g., 4-chlorophenyl, 4-nitrophenyl, 4-aryloxy-aryl, e.g., 4-phenoxyphenyl, 4-alkoxyphenyl, e.g., 4-methoxyphenyl, 4-(alkyl-carbonyl)-phenyl, e.g., 4-(methylcarbonyl)phenyl or in 4-(phenylcarbonyl)phenyl.
By the term "alkyl" is meant a C.sub.1 to C.sub.7 straight or branched chain hydrocarbon, preferably a C.sub.1 to C.sub.4 hydrocarbon, e.g., methyl, ethyl, propyl, isopropyl, N-butyl, etc. The alkyl group may be substituted by an aryl residue as defined above to form an arylalkyl residue, e.g., phenylethyl or 2-phenylethyl or by a haloaryl residue to form a haloarylalkyl residue, e.g., 4-bromo-phenethyl.
Certain of the monensin urethane derivatives, viz. those of formula I wherein R.sub.4 is phenethyl and their pharmaceutically acceptable salts, are produced by Streptomyces organisms designated as Strains X-14667, X-14573 and X-14575. Streptomyces sp. X-14667 was isolated from a soil sample collected from Aesculapius temple, Epidaurus, Greece. Streptomyces sp. X-14573 was isolated from a soil sample collected at the University of Arizona, Tempe, Ariz. Streptomyces sp. X-14575 was isolated from a soil sample collected in a corn field in the Catskills, N.Y., Streptomyces sp. X-14667, X-14573 and X-14575 were deposited with the United States Department of Agriculture, Agricultural Research Service, Northern Regional Research Laboratories (NRRL) Peoria, Ill. as lyophilized vials of the cultures. The cultures, given the identification numbers NRRL 11336 (X-14667), NRRL 11337 (X-14573) and NRRL 11338 (X-14575) (all deposited at NRRL on June 29, 1978) have been made available to the public through NRRL.
The cultures have also been deposited at the American Type Culture Collection, Rockville, Md. on August 23, 1979 and given the following accession numbers:
______________________________________ X-14667 ATCC 31551 X-14573 ATCC 31552 X-14575 ATCC 31553 ______________________________________
The monensin urethane derivatives are polyether antibiotics and form a variety of pharmaceutically acceptable salts. These salts are prepared from the free acid form of the antibiotics by methods well-known for compounds of the polyether type in the art; for example, by washing the free acid in solution with a suitable base or salt. Examples of such pharmaceutically acceptable basic substances capable of forming salts for the purpose of the present invention include alkali metal bases, such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkaline earth metal bases, such as calcium hydroxide, barium hydroxide and the like; and ammonium hydroxide. Alkali metal or alkaline earth metal salts suitable for forming pharmaceutically acceptable salts can include anions such as carbonates, bicarbonates and sulfates.
Examples of organic bases forming pharmaceutically acceptable salts with the polyether compounds are lower alkyl amines, primary, secondary and tertiary hydroxy lower alkylamines such as ethylamine, isopropylamine, diethylamine, methyl-n-butylamine, ethanolamine and diethanolamine.
An amine especially preferred is N-methylglucamine. Salts of N-methylglucamine are of special value because of their water-solubility which makes them amenable to parenteral use.